Is EPHA4 p.Pro505Ala (c.1513C>G) pathogenic?

EPHA4 p.Pro505Ala (c.1513C>G) is classified Uncertain significance in EPHA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-06). AlphaMissense: likely benign (0.2844); Very rare (popmax 0.00119%, nfe).

How common is EPHA4 p.Pro505Ala (c.1513C>G) in the general population?

EPHA4 p.Pro505Ala (c.1513C>G) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about EPHA4 p.Pro505Ala (c.1513C>G)?

AlphaMissense predicts likely benign (score 0.2844) — an in-silico prediction, not a clinical call.

EPHA4 p.Pro505Ala

c.1513C>G · rs1312612580 · VCV2494574

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2844 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2844	likely benign
REVEL	0.654	pathogenic-leaning
SaProt	LLR -8.86	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 142 kb · p 2.7e-22 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00119% European (non-Finnish) · 14/1,179,904 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000958% 14/1,461,704 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EPHA4
Protein: p.Pro505Ala
Coding: c.1513C>G
MANE Select: NM_004438
dbSNP: rs1312612580
Type: single nucleotide variant
Location: chr2:221456703 (GRCh38)
Gene constraint: LOEUF 0.256 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.93 · 17 PDB
Residue 505: the fibronectin type-iii 2 domain

Full EPHA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPHA4 p.Ala321Thr Uncertain significance ★★ ⚠ same type
EPHA4 p.Ala852Val Uncertain significance ★★ ⚠ same type
EPHA4 p.Arg209Cys Uncertain significance ★★ ⚠ same type
EPHA4 p.Arg230Gln Uncertain significance ★★ ⚠ same type
EPHA4 p.Arg466Gln Uncertain significance ★★ ⚠ same type
EPHA4 p.Arg466Trp Uncertain significance ★★ ⚠ same type
EPHA4 p.Arg486Gln Uncertain significance ★★ ⚠ same type
EPHA4 p.Arg573Trp Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/epha4-p-pro505ala (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown